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NEUROSCIENCE |
1 Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, D-79104 Freiburg im Breisgau Germany
2 Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, CNR, I-80078 Pozzuoli, Italy
Endocannabinoids acting on CB1 cannabinoid receptors are involved in short- and long-term depression of synaptic transmission. The aim of the present study was to determine which endocannabinoid, anandamide or 2-arachidonoylglycerol (2-AG), is involved in depolarization-induced suppression of inhibition (DSI) in the cerebellar cortex, which is the most widely studied form of short-term depression. Depolarization of Purkinje cells in the mouse cerebellum led to an increase in intracellular calcium concentration and to suppression of the inhibitory input to these neurons (i.e. DSI occurred). Orlistat and RHC80267, two blockers of sn-1-diacylglycerol lipase, the enzyme catalysing 2-AG formation, abolished DSI by acting downstream of calcium influx. In contrast, DSI occurred also in the presence of a phospholipase C inhibitor. Intact operation of the calcium-dependent messengers calmodulin and Ca2+–calmodulin-dependent protein kinase II were necessary for DSI. DSI was potentiated by an inhibitor of the main 2-AG-degrading enzyme, monoacylglycerol lipase. Interference with the anandamide metabolizing enzyme, fatty acid amide hydrolase, did not modify DSI. Thus, three kinds of observations identified 2-AG as the endocannabinoid involved in DSI in the mouse cerebellum: DSI was abolished by diacylglycerol lipase inhibitors; DSI was potentiated by a monoglyceride lipase inhibitor; and DSI was not changed by an inhibitor of fatty acid amide hydrolase. Further experiments indicated that 2-AG is the endocannabinoid mediating short-term retrograde signalling also at other synapses: orlistat abolished DSI in the rat cerebellum, DSI in the mouse substantia nigra pars reticulata and depolarization-induced suppression of excitation in the mouse cerebellum.
(Received 16 August 2006;
accepted after revision 5 September 2006;
first published online 14 September 2006)
Corresponding author B. Szabo: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität; Albertstrasse 25, D-79104 Freiburg im Breisgau, Germany. Email: szabo{at}pharmakol.uni-freiburg.de
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